Pulmonary Arterial Hypertension KnowledgeBase (PAHKB)
PAHKB
Pulmonary Arterial Hypertension KnowledgeBase
General information | Literature | Expression | Regulation | Mutation | Interaction

Basic Information

Gene ID

5160

Name

PDHA1

Synonymous

PDHA|PDHCE1A|PHE1A;pyruvate dehydrogenase (lipoamide) alpha 1;PDHA1;pyruvate dehydrogenase (lipoamide) alpha 1

Definition

PDHE1-A type I|pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial|pyruvate dehydrogenase complex, E1-alpha polypeptide 1

Position

Xp22.1

Gene type

protein-coding

Source

Count: PDHA1; 5160

Sentence

Abstract

Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNF? contributes to the pathogenesis of pulmonary arterial hypertension.

pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMC). This apoptosis resistance is characterized by PASMC mitochondrial hyperpolarization [in part, due to decreased pyruvate dehydrogenase (PDH) activity], decreased mitochondrial reactive oxygen species (mROS), downregulation of Kv1.5, increased [Ca(++)](i), and activation of the transcription factor nuclear factor of activated T cells (NFAT). Inflammatory cells are present within and around the remodeled arteries and patients with PAH have elevated levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNFalpha). We hypothesized that the inflammatory cytokine TNFalpha inhibits PASMC PDH activity, inducing a PAH phenotype in normal PASMC. We exposed normal human PASMC to recombinant human TNFalpha and measured PDH activity. In TNFalpha-treated cells, PDH activity was significantly decreased. Similar to exogenous TNFalpha, endogenous TNFalpha secreted from activated human CD8(+) T cells, but not quiescent T cells, caused mitochondrial hyperpolarization, decreased mROS, decreased K(+) current, increased [Ca(++)](i), and activated NFAT in normal human PASMC. A TNFalpha antibody completely prevented, while recombinant TNFalpha mimicked the T cell-induced effects. In vivo, the TNFalpha antagonist etanercept prevented and reversed monocrotaline (MCT)-induced PAH. In a separate model, T cell deficient rats developed less severe MCT-induced PAH compared to their controls. We show that TNFalpha can inhibit PASMC PDH activity and induce a PAH phenotype. Our work supports the use of anti-inflammatory therapies for PAH.

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